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Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis.

Yu M, Wang C, Kyle AF, Jakubec P, Dixon DJ, Schrock RR, Hoveyda AH - Nature (2011)

Bottom Line: Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM.The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity.As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA.

ABSTRACT
Many natural products contain a C = C double bond through which various other derivatives can be prepared; the stereochemical identity of the alkene can be critical to the biological activities of such molecules. Catalytic ring-closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, cyclizations often proceed without control of alkene stereochemistry. This shortcoming is particularly costly when the cyclization reaction is performed after a long sequence of other chemical transformations. Here we outline a reliable, practical and general approach for the efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% of the Z isomer owing to control induced by a tungsten-based alkylidene. Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM. The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity. As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.

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Two cases in natural product total synthesis where catalytic RCM with some of the most commonly used complexes (1, 2b–d) affords the macrocyclic alkene with minimal stereoselectivity and often with a preference for generation of the undesired E isomerDifficulties in stereoselective ring closure are particularly detrimental since the catalytic RCM takes place late in the synthesis route, inflicting substantial loss in efficiency. For example, diene 3, used in the total synthesis of anti-cancer agent epothilone C, is prepared by a 16-step sequence. TBS = t-butyldimethylsilyl; Boc = t-butoxycarbonyl.
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Figure 1: Two cases in natural product total synthesis where catalytic RCM with some of the most commonly used complexes (1, 2b–d) affords the macrocyclic alkene with minimal stereoselectivity and often with a preference for generation of the undesired E isomerDifficulties in stereoselective ring closure are particularly detrimental since the catalytic RCM takes place late in the synthesis route, inflicting substantial loss in efficiency. For example, diene 3, used in the total synthesis of anti-cancer agent epothilone C, is prepared by a 16-step sequence. TBS = t-butyldimethylsilyl; Boc = t-butoxycarbonyl.

Mentions: The severe shortcoming in the state-of-the-art is illustrated by the two sets of non-selective catalytic RCM, shown in Fig. 1, performed en route to macrocyclic natural products epothilone Ciii,iv,v and nakadomarin Avi. Efforts from several laboratories have focused on catalytic RCM for synthesis of the macrocyclic moiety of different members of the epothilone family; popular catalysts, like those derived from alkylidene 1vii and carbenes 2a–dviii,ix (Fig. 1), deliver little or no stereoselectivityx,xi. Initiatives regarding nakadomarin A (cf. 5→6, Fig. 1), consisting of four different routes that incorporate a late-stage catalytic macrocyclic ring closure, have met with equally unsatisfactory outcomesxii,xiii,xiv,xv.


Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis.

Yu M, Wang C, Kyle AF, Jakubec P, Dixon DJ, Schrock RR, Hoveyda AH - Nature (2011)

Two cases in natural product total synthesis where catalytic RCM with some of the most commonly used complexes (1, 2b–d) affords the macrocyclic alkene with minimal stereoselectivity and often with a preference for generation of the undesired E isomerDifficulties in stereoselective ring closure are particularly detrimental since the catalytic RCM takes place late in the synthesis route, inflicting substantial loss in efficiency. For example, diene 3, used in the total synthesis of anti-cancer agent epothilone C, is prepared by a 16-step sequence. TBS = t-butyldimethylsilyl; Boc = t-butoxycarbonyl.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3211109&req=5

Figure 1: Two cases in natural product total synthesis where catalytic RCM with some of the most commonly used complexes (1, 2b–d) affords the macrocyclic alkene with minimal stereoselectivity and often with a preference for generation of the undesired E isomerDifficulties in stereoselective ring closure are particularly detrimental since the catalytic RCM takes place late in the synthesis route, inflicting substantial loss in efficiency. For example, diene 3, used in the total synthesis of anti-cancer agent epothilone C, is prepared by a 16-step sequence. TBS = t-butyldimethylsilyl; Boc = t-butoxycarbonyl.
Mentions: The severe shortcoming in the state-of-the-art is illustrated by the two sets of non-selective catalytic RCM, shown in Fig. 1, performed en route to macrocyclic natural products epothilone Ciii,iv,v and nakadomarin Avi. Efforts from several laboratories have focused on catalytic RCM for synthesis of the macrocyclic moiety of different members of the epothilone family; popular catalysts, like those derived from alkylidene 1vii and carbenes 2a–dviii,ix (Fig. 1), deliver little or no stereoselectivityx,xi. Initiatives regarding nakadomarin A (cf. 5→6, Fig. 1), consisting of four different routes that incorporate a late-stage catalytic macrocyclic ring closure, have met with equally unsatisfactory outcomesxii,xiii,xiv,xv.

Bottom Line: Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM.The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity.As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA.

ABSTRACT
Many natural products contain a C = C double bond through which various other derivatives can be prepared; the stereochemical identity of the alkene can be critical to the biological activities of such molecules. Catalytic ring-closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, cyclizations often proceed without control of alkene stereochemistry. This shortcoming is particularly costly when the cyclization reaction is performed after a long sequence of other chemical transformations. Here we outline a reliable, practical and general approach for the efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% of the Z isomer owing to control induced by a tungsten-based alkylidene. Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM. The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity. As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.

Show MeSH
Related in: MedlinePlus